The present invention relates to an oral pharmaceutical composition containing a polyethylene glycol-immunoglobulin, particularly polyethylene glycol-immunoglobulin G (PEG-IgG) conjugate and to the oral administration of a PEG-Ig conjugate to patients with gastrointestinal secretory immunodeficiency to reconstitute secretory immunity.
The components of the gastrointestinal immune system consist of lymphoid tissues concentrated in Peyer's patches, intraepithelial lymphocytes, phagocytic cells, antibodies, and complement components. Secretory IgA is the major antibody in the gastrointestinal system. It differs from serum IgA by the presence of two additional polypeptide chains, a J chain and a secretory component. Because of this additional structure, secretory IgA resists proteolytic digestion.
Secretory immune deficiency is a commonly encountered disorder that arises from a variety of congenital, physiologic, or pathologic mechanisms. Infants normally have secretory IgA deficiency since IgA is produced in only very low amounts for the first few months of life. (This condition is remedied when the infants receive their mother's milk which contains secretory IgA.) Additionally, patients with selective IgA deficiency or common variable immunodeficiency also have a deficiency of IgA. Patients undergoing chemotherapy and radiation suffer the destruction of IgA producing plasma cells resulting in secondary secretory IgA deficiency. Further instances of acquired persistent secretory IgA deficiency occur, e.g., in bone marrow transplant recipients, and in acquired immunodeficiency due to HIV infection.
As is apparent from the effectiveness of mother's milk in overcoming secretory IgA deficiency in infants, oral administration of the antibody can provide therapeutic advantages. Human milk, and especially human colostrum, might provide the ideal form of immunoglobulin for oral use, but there are major difficulties in the procurement, preparation, sterilization, and standardization of this substance. In addition, there is the possibility that banked breast milk could transmit viral infections.
A few studies have been done to assess the oral use of commercially available pooled human serum immunoglobulin to reconstitute secretory immunity (see Table 1). While these studies report some success, the stability of serum immunoglobulin in the gastrointestinal tract is questionable because of proteolytic digestion of the unprotected serum immunoglobulins. Enzymes such as trypsin and pepsin attack serum immunoglobulins and render them ineffective against immunologically undesirable materials such as bacteria.
It is the object of the present invention to provide an oral pharmaceutical composition which can be made from pooled human serum immunoglobulin G or serum IgA that resists proteolytic digestion and thus a convenient means to reconstitute secretory immunity in patients with gastrointestinal immunodeficiency through the oral administration.